PROJECT SUMMARY Fibrosis involving the airways, vasculature, alveoli, and pleura is seen, to varying degrees, in a number of clinical syndromes, including asthma, subphenotypes of chronic obstructive pulmonary disease, pulmonary hypertension, and idiopathic pulmonary fibrosis (IPF). IPF is the most enigmatic and fatal of the fibrotic lung disorders. Despite the recent approval of two drugs, survival has not significantly improved. Pulmonary fibrosis represents a complex tissue response to lung injury that involves a number of cell types, mediators, and signaling pathways. In just over the last few years, several new concepts in disease pathogenesis have emerged; these include metabolic reprogramming, epigenetics, immune modulation, macrophage biology and the invasive/apoptosis-resistant phenotype of myofibroblasts (myoFbs). Each of these concepts/paradigms is addressed in this renewal application of this tPPG. Work conducted during Cycle I of this tPPG has validated the pro-fibrotic effects of the reactive oxygen species (ROS)-regenerating enzyme, NADPH oxidase 4 (NOX4), and identified circulating plasma biomarkers of oxidative stress in human subjects with IPF. In Project 1, we will conduct a Phase IIb clinical trial of the safety and efficacy of a NOX1/4 inhibitor in IPF using multiple biomarkers and physiologic measures as primary and secondary end-points. Project 2 will test the hypothesis that redox-metabolic reprogramming of myoFbs accounts for the observed pro-fibrotic effects of NOX4. Based on emerging data on macrophage-myoFb interactions in fibrosis, Project 3 will test the hypothesis that NOX4 modulates macrophage mitochondrial ROS and metabolism to polarize alveolar macrophages to a pro-fibrotic phenotype. Project 4 will test the novel hypothesis that B-cell derived autoantibodies epigenetically reprogram Fbs to an anti-apoptotic phenotype. Together, this tPPG will elucidate critical links between cellular redox control and metabolic reprogramming, uncover novel regulatory mechanisms of macrophage polarization, and illuminate previously unrecognized connections between innate/adaptive immunity, epigenetics and lung fibrosis. Importantly, this tPPG will advance a novel anti-fibrotic drug therapy that more specifically targets redox biology in IPF, which will enable future Phase III clinical trials.